YM872, a novel selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, reduces brain damage after permanent focal cerebral ischemia in cats.
YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3, 4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate), a selective, potent and highly water-soluble competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, was investigated for its neuroprotective effect against focal cerebral ischemia in halothane-anesthetized cats. Cats were subjected to permanent occlusion of the left middle cerebral artery for 6 h, then sacrificed and examined histologically. The electroencephalogram and cerebral blood flow were monitored. Intravenous infusion of YM872 starting 10 min after the onset of ischemia at a rate of 2 mg/kg/h for 6 h markedly reduced the volume of ischemic damage by 61% (from 2604 +/- 202 mm3 of the cerebral hemisphere in saline-treated cats to 1025 +/- 277 mm3 in YM872-treated cats; P < .01), as assessed in 12 stereotaxically determined coronal sections. No significant differences were observed between YM872- and saline-treated cats concerning physiological variables including brain temperature. No precipitation of YM872 in the kidney was seen in any YM872-treated animal. The present data further support the notion that the AMPA receptor plays an important role in the progression of focal ischemic damage in a gyrencephalic model. This evidence for the neuroprotective efficacy of YM872 suggests its therapeutic potential in the treatment of acute stroke in humans.
Takahashi
M
M
Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 305, Japan.
Ni
J W
JW
Kawasaki-Yatsugi
S
S
Toya
T
T
Yatsugi
S I
SI
Shimizu-Sasamata
M
M
Koshiya
K
K
Shishikura
J I
JI
Sakamoto
S
S
Yamaguchi
T
T
D000818:Animals; D001921:Brain / Q000098:blood supply; D002545:Brain Ischemia / Q000188:drug therapy*; D002415:Cats; D002540:Cerebral Cortex / Q000098:blood supply; D003342:Corpus Striatum / Q000098:blood supply; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents; D011810:Quinoxalines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects
D007093:Imidazoles; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; C110629:YM 872